Doxorubicin Bidiphar: Anthracycline cancer treatment drug

2021-07-04 05:27 PM

Doxorubicin is an anthracycline antineoplastic agent that can be used alone or in combination with other antineoplastic agents. Cross-resistance occurs when the tumor is resistant to both doxorubicin and daunorubicin.

Producer

Bidiphar.

Ingredient

Per mL: Doxorubicin hydrochloride 2mg.

Pharmacodynamic

Pharmacotherapeutic group

Anthracycline anti-cancer drug.

ATC code: L01DB01.

Pharmacology and mechanism of activation

Doxorubicin is a cytotoxic anthracycline antibiotic isolated from the culture of Streptomyces peucetius var. caecius. Currently synthesized from daunorubicin. Doxorubicin is a strong tissue irritant and can cause tissue necrosis, for example in the case of extravascular injection.

The biological activity of doxorubicin is due to doxorubicin binding to DNA inhibiting enzymes required for DNA replication and transcription. Doxorubicin strongly disrupts the cell cycle in the mitotic S and mitotic phases, but it also acts on other phases of the cell cycle.
 
Doxorubicin can be used alone or in combination with other anticancer drugs. Cross-resistance occurs when the tumor is resistant to both doxorubicin and daunorubicin.

Pharmacokinetics

The metabolism and distribution of doxorubicin is still being elucidated. Doxorubicin is metabolized mainly in the liver to doxorubicinol and aglycones. It should be noted that some of these metabolites are also cytotoxic but not more toxic than doxorubicin. High concentrations of metabolites appear rapidly in plasma and pass through the distribution phase with a short half-life. Slow metabolism in people with reduced liver function. After being injected into a vein, doxorubicin quickly leaves the blood and enters tissues, especially the lungs, liver, heart, spleen, and kidneys. The volume of distribution of doxorubicin hydrochloride given intravenously is approximately 700-1100 liters/m2. In plasma about 70% of doxorubicin is bound to proteins. Doxorubicin crosses the blood-brain barrier very little, but the drug crosses the placental barrier.

The drug is rapidly metabolized in the liver, forming metabolites, including the active substance (adriamycinol). Within 5 days of taking the drug, about 5% of the dose is excreted by the kidneys; Within 7 days, about 40-50% is eliminated via bile. If liver function is reduced, elimination is slower, so the dose should be reduced. The graph of the decrease in doxorubicin concentration in the blood has 3 phases: the mean half-life is 12 hours, 3.3 hours and about 30 hours.
 
Doxorubicin should not be taken orally because of its very low bioavailability (less than 5%).

Indications and uses

Doxorubicin is indicated for the treatment of the following cancers:

Small cell lung cancer (SCLC).

Breast cancer.

Advanced epithelial ovarian cancer.

Bladder cancer (using an infusion of drugs into the bladder).

Money to support and support the treatment of malignant bone tumors.

Advanced soft tissue sarcoma in adults.

Sarcom Ewing.

There are two types of malignant lymphomas: Hodgkin's and non-Hodgkin's.

Acute lymphocytic leukemia.

Acute myeloid leukemia.

Progressive multiple myeloma.

Advanced or recurrent endometrial cancer.

U Wilm.

Advanced (follicular, papillary) thyroid cancer.

Undifferentiated thyroid cancer.

Advanced neuroblastoma.

Metastatic gastric cancer.

Doxorubicin is commonly used in chemotherapy regimens in combination with other cytotoxic drugs.

Dosage and Administration

Amount

Intravenous injection

The dose of doxorubicin depends on the treatment regimen, general condition and previous treatment of the patient. The dosage regimen of doxorubicin hydrochloride may vary according to the indication (solid tumors or acute leukemia) and to specific treatment regimens (such as single dose or in combination with toxic agents). other cells or as part of a treatment procedure that combines multiple methods including: a combination of chemotherapy, surgery, radiation therapy, and hormonal therapy).

Monotherapy

Dosage is calculated on the basis of body surface area (mg/m2). The recommended dose as monotherapy is 60-75 mg/m2 body surface area every 3 weeks.

Combination sketch

When doxorubicin is used in combination with other antineoplastic agents with overlapping toxicity, such as high-dose intravenous cyclophosphamide or anthracycline compounds (e.g., daunorubicin, idarubicin and/or epirubicin), the dose of doxorubicin should be reduce to 30-60 mg/m2 every 3-4 weeks.

For patients who cannot receive adequate therapy (e.g. immunocompromised, elderly), the alternate dose is 15-20 mg/m2 body surface area per week.

Bladder path

Doxorubicin may be administered by drip into the bladder for the treatment of superficial bladder cancer or for the prevention of cancer recurrence following transurethral resection in patients at high risk of recurrence. The recommended dose for the treatment of superficial bladder cancer is a 30-50 mg intravenous drip in 25-50 mL of 0.9% NaCl solution. The optimal concentration is about 1 mg/mL. Normally, this solution should be kept in the bladder for 1-2 hours. During this phase, the patient should be rotated 90° every 15 minutes. Patients should not drink any liquids for 12 hours prior to treatment to avoid unwanted dilution of the drug with urine. This can reduce urine output by about 50 mL/hour. The drip infusion can be repeated in about 1 week to 1 month depending on whether the goal is prophylactic or curative.

Dose adjustment in special subjects

Patients with impaired liver function

Because doxorubicin is eliminated primarily by the liver and bile, its elimination may be reduced in patients with impaired liver function or biliary obstruction and this may cause serious secondary effects.

The recommendations for dose adjustment in patients with impaired liver function are based on serum bilirubin levels:

Bilirubin concentration 20-50 μmol/L: normal dose

Bilirubin levels >50 μmol/L: normal dose

Doxorubicin is contraindicated in patients with severe hepatic impairment.

Patients with impaired renal function

In patients with renal impairment (GFR < 10 mL/min), only 75% of the normal dose should be used.

To avoid the risk of cardiomyopathy, the cumulative total dose of doxorubicin (including daunorubicin analogues) should not exceed 450-550 mg/m2 body surface area. If patients with cardiac disease are concurrently receiving cardiac and/or mediastinal irradiation, prior treatment with an alkylating agent, and in high-risk patients (with >5 years of arterial hypertension, with muscle damage Cardiac, valvular or precoronal, over 70 years), the maximum total dose of 400 mg/m2 should not be exceeded and cardiac function of these patients should be monitored.

Patient with heart failure

Discontinue doxorubicin in patients with signs or symptoms of cardiomyopathy.

Dosage in children

Dosage in children should be reduced because children are at greater risk for cardiotoxicity, especially late toxicity. Bone marrow disease should be anticipated for a minimum of 10 to 14 days after initiation of therapy. The maximum cumulative dose in children is 400 mg/m2.

Obese patient

Reducing the starting dose or prolonging the dosing cycle should be considered in obese patients.

How to use

Doxorubicin injection should be used under the supervision of a physician qualified and experienced in the treatment of cytotoxicity. In addition, patients must be carefully and regularly monitored during treatment.

Because of the risk of often fatal cardiomyopathy, the patient's risks and benefits should be considered prior to treatment.
 
Doxorubicin is administered intravenously and infused into the bladder; should not be administered orally, subcutaneously, intramuscularly or intramedullary. Doxorubicin can be given as a rapid intravenous infusion (bolus) over several minutes or as an intravenous infusion up to 1 hour or as a continuous intravenous infusion for up to 96 hours.

The drug solution is introduced into the flowing intravenous line of 0.9% NaCl solution or 5% dextrose solution over about 2-15 minutes. This technique helps to minimize the risk of thrombophlebitis and extravasation out of the veins, which can lead to "orange peels", blisters, and severe local tissue necrosis. The direct intravenous technique is not recommended due to the risk of extravasation.

Instructions for safe use and disposal: Doxorubicin is a potent cytotoxic agent and should only be prescribed, prepared and used only by professionals trained in the safe use of the preparation. this. The following guidelines should be followed when handling, preparing, and discarding doxorubicin.

Prepare

Staff must be trained with good technique to handle.

Pregnant staff should not work with this cytotoxic drug.

Personnel handling doxorubicin must wear protective equipment: goggles, gown, disposable gloves and mask.

All items used for infusion or cleaning, including gloves, must be placed in hazardous waste bags for high temperature (700°C) incineration.

All cleaning materials must be handled as described above.

Always wash your hands after removing gloves.

Drug infection

In case of contact with skin or mucous membranes, wash the exposed area thoroughly with soap and water or sodium bicarbonate solution. However, avoid scrubbing the skin with a brush. A soothing cream may be used to reduce transient soreness in the skin.

In case of eye contact, pull up the affected eyelid and flush the eye with plenty of water for at least 15 minutes or 0.9% sodium chloride solution for injection. Then take it to a doctor for a medical evaluation.

If the drug is spilled or leaked, it must be treated with 1% sodium hypochloride solution or simpler with phosphate buffer (pH > 8) until the solution becomes discolored. Use an absorbent towel/cloth to keep in the affected area. Wash twice with water. Place all towels in a plastic bag and seal to incinerate.

Use

The remainder of the drug as well as all items used for dilution and infusion should be disposed of according to standard hospital procedures for cytotoxic agents in accordance with applicable regulations. related to hazardous waste disposal.

Handling

Use only 1 time. Any unused medication or waste should be disposed of as required at the hospital. Follow instructions for handling cytotoxic drugs.

Use caution

Doxorubicin injection should only be used under the supervision of a physician experienced in the treatment of cytotoxicity by intravenous or bladder administration. Doxorubicin may increase the toxicity of other anticancer therapies. Careful management of clinical complications should be exercised, particularly in elderly patients, patients with a history of heart disease or bone marrow suppression, or patients previously treated with derivatives. anthracyclines or treated with radiation to the mediastinum.

Close observation of the patient's condition and follow-up with general trials is required during initial therapy. It is therefore recommended that patients be hospitalized at least during the initial phase of treatment. Doxorubicin can cause infertility while taking the drug.

Patients should recover from prior treatment-induced acute toxicity (eg, stomatitis, neutropenia, thrombocytopenia, and systemic infection) before initiating doxorubicin therapy.

Before or during treatment with doxorubicin, the following tests are recommended (frequency of tests depends on general condition, dose, and concomitant medications):

Chest and chest X-ray, electrocardiogram (ECG).

Regularly monitor cardiac function: left ventricular ejection fraction (LVEF) by ECG, UCG and MUGA scan.

Check the oral cavity and pharynx daily for mucosal changes.

Blood tests: hematocrit, platelets, leukocyte differentiation, SGPT, SGOT, LDH, bilirubin, uric acid.

Treatment control

Before treatment, liver function should be measured with routine tests such as AST, ALT, ALP and bilirubin as well as kidney function.

Control left ventricular function

Analysis of LVEF by echocardiography or cardiac scintigraphy should be performed to assess the patient's cardiac status. This control should be performed before starting treatment and after each cumulative dose (approximately 100 mg/m2).

Heart function

Cardiotoxicity is a risk of anthracycline therapy and may present with early (acute) or late (delayed) events.

Early (acute) events

Early doxorubicin-induced cardiotoxicity includes predominantly sinus tachycardia and/or ECG abnormalities such as atypical ST-T wave changes. Tachyarrhythmias, including premature ventricular contraction, ventricular tachycardia, bradycardia as well as atrioventricular block and bundle branch block have also been reported. These symptoms are usually transient acute toxicity. These symptoms are usually not predictive of further progression of late cardiotoxicity and do not usually require discontinuation of the drug. Widening and flattening of the QRS wave complex beyond normal limits may be indicative of doxorubicin-induced cardiomyopathy. As a rule, patients with a normal baseline LVEF value (= 50%), a 10% decrease in absolute value, or a fall below the 50% threshold indicates cardiac dysfunction, and in this condition, Treatment with doxorubicin should be considered with caution.

Late (delayed) events

Late cardiotoxicity usually occurs at the end of doxorubicin therapy or within 2 to 3 months after drug discontinuation. Some events of slower onset (months to years) have been reported. Late cardiomyopathy is manifested by decreased left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as dyspnoea, pulmonary edema, postural edema, enlarged heart, and liver enlargement, oliguria, ascites, pleural effusion, and galloping rhythm. Subacute manifestations such as pericarditis/myocarditis have also been reported. Life-threatening congestive heart failure is the most serious form of cardiomyopathy associated with anthracycline use and represents a cumulative dose-limiting toxicity.

Cardiac function should be assessed prior to initiating therapy with doxorubicin and cardiac function should be monitored during treatment to minimize the risk of severe heart failure. The risk of heart failure can be reduced with regular monitoring of LVEF during treatment and discontinuation of doxorubicin at the first symptom of heart failure. The appropriate quantitative method for assessing cardiac function (evaluating LVEF) is multiport angiography (MUGA) or echocardiography (ECHO). Initial assessment of cardiac function by electrocardiogram and MUGA or ECHO is recommended, especially in patients with risk factors that increase the risk of cardiotoxicity. LVEF should be re-evaluated with MUGA or ECHO, particularly when high-dose, cumulative anthracycline derivatives are used. The method used to assess cardiac function should be consistent during follow-up.

The probability of developing congestive heart failure, estimated at 1-2% at the cumulative dose of 300 mg/m2, increases slowly to a total cumulative dose of 450-550 mg/m2. Thereafter, the risk of developing congestive heart failure rapidly increases and a maximum cumulative dose of 550 mg/m2 is not recommended. If the patient has other potential risk factors for cardiotoxicity (history of cardiovascular disease, previous treatment with other anthracyclines or anthracendions, prior radiotherapy or concurrent mediastinal radiotherapy). pericardial/pericardial and concomitant use of drugs that may decrease myocardial contractility including: cyclophosphamide and 5-fluoruracil), doxorubicin-induced cardiotoxicity may occur at lower cumulative doses and cardiac function should be carefully monitored.

Children and adolescents are at increased risk for late development of cardiotoxicity following doxorubicin administration. Women are at higher risk than men. Periodic cardiac function evaluation is recommended to monitor this effect.

Toxicity of doxorubicin and anthracycline or anthrace derivatives.

Liver function

The major route of elimination of doxorubicin is via the hepatobiliary system. The total bilirubin level should be assessed before and during treatment with doxorubicin. Patients with hyperbilirubinemia may have a slower clearance rate, with an increased risk of toxicity. A low dose is recommended for these patients. Patients with severe hepatic impairment should not take doxorubicin.

Hematological toxicity

Doxorubicin can cause myelosuppression. Hematologic parameters should be checked before and during each cycle of doxorubicin therapy, including differentiated leukocytes. A dose-dependent and reversible neutropenia and/or agranulocytosis (neutropenia) is the main manifestation of doxorubicin hematologic toxicity and is the most common acute toxicity of limited dose when using this medicine. Leukopenia and neutropenia are usually at their lowest between the 10th and 14th days after dosing. WBC/neutrophil counts return to normal by day 21 in most patients. A dose reduction or an increase in dosing interval should be considered if hematological values ​​are abnormal. Thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include: fever, sepsis, sepsis, septic shock, hemorrhage, tissue hypoxia, or death.

Secondary Leukemia

Secondary leukemia with or without a pre-leukemic phase has been reported in patients treated with anthracyclines including doxorubicin. Secondary leukemia is more common when used in combination with DNA-damaging antineoplastic agents, when the patient has been previously treated with high doses of cytotoxic drugs, or when the dose of anthracyclines is rapidly increased. Leukemia can be incubated for 1 to 3 years.

Infusion into the bladder

Doxorubicin may cause symptoms of drug-induced cystitis (dysuria, urinary frequency, nocturia, urinary frequency, hematuria, necrosis of the bladder wall). Special attention should be paid to cases involving urinary catheterization (such as urethral obstruction due to a large tumor inside the bladder). Bladder catheterization is contraindicated for tumors that have invaded the bladder.

The intravesical line should not be treated in patients with invasive tumors that have infiltrated the bladder wall, urinary tract infections, and cystitis.

Control serum uric acid

During treatment, uric acid may increase. In this case, uric acid lowering therapy should be instituted.

In patients with severe renal impairment, dose reduction is necessary.

Effects on the gastrointestinal tract

Prophylactic antiemetics are recommended.

Note: Doxorubicin should not be used in the presence of inflammation, ulcers or diarrhea.

Out of circuit

Extravasation of doxorubicin solution after infusion can cause local necrosis, thrombophlebitis. A burning sensation at the infusion site is a sign of extravasation. If extravasation occurs, the injection or infusion should be stopped immediately, the needle should be kept for a short time, then withdrawn after a short time of retraction. In case of extravasation, start intravenous infusion of dexrazoxan, no later than 6 hours after extravasation. In cases where dexrazoxan is contraindicated, topical application of dimethyl sulfonide (DMSO) to twice the area of ​​extravasation is recommended and repeated 3 times daily for not less than 14 days. Surgical removal of the necrotic portion may be performed if necessary. Due to the antagonism mechanism, the applied area should be cooled after application of DMSO to relieve pain. DMSO should not be used in patients receiving dexrazoxan for extravasation.

Radiotherapy

Radiation toxicity (to the myocardium, mucosa, skin and liver) has also been reported. Particular caution is required for patients who have received prior radiation therapy or are receiving concurrent radiation therapy or are scheduled to receive radiation therapy. These patients are at particular risk of local reactions (recurrence) if doxorubicin hydrochloride is used. Severe, sometimes fatal, hepatotoxicity (liver damage) has been reported with combined use. Prior radiotherapy to the mediastinum increases the cardiotoxicity of doxorubicin. The cumulative dose of 400 mg/m2 should not be exceeded in this case.

Infertility

Doxorubicin may be genotoxic. Doxorubicin can cause infertility while taking the drug. In women, doxorubicin can cause amenorrhea. Early menopause may occur, although ovulation and menstruation return after treatment ends. Females should not become pregnant during and for 6 months after treatment.

Doxorubicin is mutagenic and can cause chromosomal damage in male sperm. Low sperm count or no sperm at all can be permanent. However, in some cases, sperm counts are reported to return to normal spermatogenesis levels. This effect can occur several years after the end of treatment. Men being treated with doxorubicin should use effective contraception. At the same time, it is not advisable to have children while taking the drug and for up to 6 months after finishing treatment. If possible, sperm should be preserved because the patient is at risk of irreversible infertility due to the use of the drug.

Anti-cancer therapy

Doxorubicin may increase the toxicity of other anticancer treatments. Exacerbations of hemorrhagic cystitis due to cyclophosphamide and increased hepatotoxicity due to 6-mercaptopurine have been reported. As with other cytotoxic drugs, doxorubicin has been reported to cause thrombophlebitis and thromboembolic events including pulmonary embolism (some fatal).

Vaccine

Doxorubicin should be avoided in combination with vaccine preparations containing live or attenuated bacteria. Use should be avoided in patients recently vaccinated against polio. Administration of live or attenuated vaccine preparations to patients who are immunocompromised by chemotherapy drugs such as doxorubicin can cause severe infection and even death. Vaccine preparations containing killed or inactivated bacteria may be used. However, reactions to these vaccines may be mild.

Other

Clearance of doxorubicin is reduced in obese patients (eg, > 130% of ideal body weight).

Tumor lysis syndrome

Doxorubicin can cause hyperuricemia due to strong catabolism of purine and rapid lysis of cancer cells (tumor lysis syndrome). Blood levels of uric acid, potassium, calcium phosphate and creatinine should be checked after starting treatment. Rehydration, alkalinization, and prophylaxis with allopurinol may help reduce the risk of complications from tumor lysis syndrome.

A burning or stinging sensation at the injection site may indicate a small degree of extravasation. If extravasation is suspected or occurs, the injection should be stopped and re-injected in another vessel. Cooling the extravasated area for 24 hours can reduce discomfort. Patients should be carefully monitored for several weeks. If necessary, surgery can be performed.

Doxorubicin can turn urine red. Patients should be warned that this does not pose any health hazard.

The same dose should not be repeated in the presence or progression of bone marrow suppression or oral ulceration. Mouth ulcers may be preceded by a herald burning sensation in the mouth and recurrence of these symptoms is not recommended.

Effects of drugs on driving and operating machinery

Doxorubicin can cause nausea, vomiting, dizziness and drowsiness which may temporarily reduce the ability to drive and use machines.

Overdose

Clinical symptoms

Symptoms of overdose are similar to those of doxorubicin. Single doses of 250 and 500 mg have been fatal. Overdose can cause acute myocardial failure within 24 hours and cause severe myelosuppression, the strongest effect after 10-15 days of use.

Heart failure may occur slowly (6 months after overdose). Patients should be carefully monitored, if symptoms appear, they must be treated immediately.

To solve

Symptomatic supportive treatment, special attention should be paid to treatment and prevention of possible serious complications such as bleeding, severe infection, prolonged bone marrow depression. Blood transfusion and careful patient care.

Contraindications

Hypersensitivity to doxorubicin hydrochloride or to any of the excipients.

Pregnancy and lactation period.

Contraindicated for intravenous use

Hypersensitivity to anthracyclines or other anthracyclines.

Chronically manifest bone marrow depression and/or severe stomatitis caused by previous treatment with other cytotoxic drugs and/or irradiation.

Prior treatment with maximal cumulative doses of doxorubicin and/or other anthracyclines (eg, daunorubicin, epirubicin, idarubicin) and anthracyclines.

Systemic infection.

Severe liver failure.

Severe arrhythmia, heart failure, previous myocardial infarction, acute inflammatory heart disease.

Tendency to increase bleeding.

Breastfeeding women.

Contraindications when using the bladder path

Invasive tumors invade the bladder.

Cystitis.

Blood in urine.

Difficulty instituting urinary catheters (such as large tumors in the bladder).

Breastfeeding women.

Urinary tract infections.

Patients with AIDS-related Kaposi cancer are effectively treated with alpha-interferon systemic or topical therapy.

Use in pregnant and lactating women

Pregnancy period

Doxorubicin causes fetal defects and is often severe, so the use of doxorubicin must be extremely limited after weighing the benefit to the mother and the harm to the child.

Breastfeeding period

Doxorubicin is excreted in milk and may cause immunosuppression, cancer, leukopenia and effects on infant growth. Lactating women who need to be treated with doxorubicin must wean their babies.

Interactive

Doxorubicin-induced cardiotoxicity is increased with previous or concomitant use of other anthracyclines or other potentially cardiotoxic drugs (such as 5-fluorouracil, cyclophosphamide, or paclitaxel) or with drugs affecting cardiac function (such as calcium antagonists, propranolol). When doxorubicin is used together with the above agents, cardiac function must be carefully monitored.

Doxorubicin co-administered with actinomycin-D and plicamycin resulted in death from cardiomyopathy.

Use of trastuzumab in combination with anthracyclines (such as doxorubicin) is associated with a high risk of cardiotoxicity. Trastuzumab and anthracyclines should not be used in combination during this time, except in well-controlled clinical studies where cardiac function is monitored. When anthracyclines are used after the end of treatment with trastuzumab, there may be an increased risk of cardiotoxicity. The half-life of trastuzumab is approximately 28-38 days and may persist in the systemic circulation for up to 27 weeks. If possible, anthracyclines should be avoided for up to 27 weeks after stopping trastuzumab. Careful monitoring of cardiac function is imperative.

Doxorubicin-induced hepatotoxicity may be augmented by other hepatotoxic treatments (eg, 6-mercaptopurine, azathioprine).

Doxorubicin is metabolised via cytochrome P450 (CYP450) and is a substrate for the transport protein Pgp. Concomitant use of CYP450 and/or Pgp inhibitors may increase plasma concentrations of doxorubicin and thereby increase toxicity. In contrast, co-administration of CYP450 inducers, such as rifampicin and barbiturates, may decrease plasma doxorubicin concentrations and impair efficacy.

Ciclosporin, an inhibitor of CYP3A4 and Pgp, increased the AUC of doxorubicin and doxorubicinol by 55% and 350%, respectively. This combination may require a dose adjustment. Cimetidine has also been shown to decrease plasma clearance and increase the AUC of doxorubicin.

Administration of doxorubicin after a short period of paclitaxel administration may decrease clearance and increase plasma concentrations of doxorubicin. Some data suggest that this interaction is less likely to be detected when doxorubicin is administered before paclitaxel.

Barbiturates can rapidly increase the plasma clearance of doxorubicin. During simultaneous use with phenytoin may reduce the concentration of phenytoin in the blood plasma.

Increased serum doxorubicin concentrations have been reported following co-administration of doxorubicin and ritonavir.

The toxic effects of doxorubicin therapy may be increased in combination with other cytostatics (eg, cytarabine, cisplatin and cyclophosphamide). Large bowel necrosis with severe bleeding and severe infection may occur when cytarabine is co-administered.

Clozapine may increase the risk and severity of hematologic toxicity due to doxorubicin.

Significant nephrotoxicity due to amphotericin B may occur during treatment with doxorubicin.

Because doxorubicin is rapidly metabolised and eliminated primarily via the biliary system, the concomitant use of known hepatotoxic chemotherapeutic agents (eg, mercaptopurine, methotrexate, streptozocin) may increase the toxicity of doxorubicin. doxorubicin as a result of reduced hepatic clearance. Doxorubicin dose adjustment is required if concomitant therapy with hepatotoxic drugs is initiated.

Doxorubicin is a potent radiosensitizer ("radio sensitizer") and the phenomena associated with it may be life-threatening. Any prior, concurrent or subsequent radiation therapy may increase doxorubicin-induced cardiotoxicity or hepatotoxicity. This also occurs for concomitant therapies with other cardiotoxic or hepatotoxic drugs.

Doxorubicin may worsen hemorrhagic cystitis caused by previous cyclophosphamide treatment.

Doxorubicin may increase serum uric acid. Therefore, it is necessary to adjust the dose of drugs that reduce uric acid.

Doxorubicin may decrease the oral bioavailability of digoxin.

During treatment with doxorubicin, the patient was not vaccinated with the live vaccine and also avoided contact with a person who had recently received a polio vaccine.

In a clinical study, a 21% increase in doxorubicin AUC was observed when administered with sorafenib 400 mg twice daily. The clinical significance of this finding is unknown.

Doxorubicin reduces absorption of ciprofloxacin but the risk of neurotoxicity is increased.

Doxorubicin inhibits the antiviral effects of stavudine.

Concomitant use of doxorubicin with other cytotoxic drugs such as warfarin may increase the effect of this drug and cause bleeding in some cases.

Verapamil potentiates the effects of doxorubicin both in tissue culture and in patients. The drug increases the concentration of doxorubicin in the blood.

Adverse Effects (ADRs)

Treatment with doxorubicin is associated with many undesirable effects, some of which are serious and require close monitoring. The frequency and type of undesirable effects are influenced by the rate of administration and the dose. Myelosuppression is an acute and dose-limiting side effect, but most are transient. The clinical consequences of doxorubicin-induced hematologic/bone marrow toxicity may be fever, sepsis, sepsis/sepsis, septic shock, hemorrhage, tissue hypoxia, or death. Nausea and vomiting as well as hair loss were seen in most patients.

The following undesirable effects have been reported in association with doxorubicin treatment

The frequencies are determined using the following convention:

Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥ 1/10,000 to < 1/1000)

Very rare (< 1/10,000).

Not known (cannot be estimated from available data).

Cautions

Incompatibilities: Doxorubicin must not be mixed with any of the following drugs (and also must not be dripped in the same line): Heparin, fluorouracil, aminophylin, cephalothin, methotrexate, dexamethasone, diazepam, hydrocortisone, furosemide.

Doxorubicin is stable in solution for infusion in combination with vincristine. A common combination in 0.9% sodium chloride solution contains doxorubicin 1.4 mg/liter and vincristine 0.33 mg/liter. Doxorubicin can also be combined with cyclophosphamide, dacarbazine, bleomycin, vinblastin.

Preservation

Protect from light, temperature 2-8°C, always keep in paper box before use.

Solution after dilution (in the concentration range of 0.05 mg/mL - 2 mg/mL) with 0.9% NaCl solution or 5% dextrose solution: 12 hours when stored at 2-8°C.

Presentation and packaging

Solution for injection 10mg/5mL: box of 1 vial of 5mL, 50mg/25mL: box of 1 vial of 25mL.